Use of mtki 1 for treating or preventing bone cancer

Abstract

The present invention is concerned with the finding that the macrocyclic quinazoline derivative 4,6-ethanediylidenepyrimido[4,5-b][6,1,12]benzoxadiazacyclo-pentadecine, 17-bromo-8,9,10,11,12,13,14,19-octahydro-20-methoxy-13-methyl-, described as compound 22 in PCT publication WO2004 / 105765, is useful in the manufacture of a medicament for the treatment or prevention of bone cancers and methods for killing bone cancer cells, including osteosarcomas, chondrosarcomas, myeloma bone disease and osteolytic bone metastases from other primary sites. It accordingly provides methods for treating, preventing, delaying or mitigating bone cancer, or for preventing and treating of bone loss associated with cancer metastases.

Description

CROSS-REFERENCE TO RELATED APPLICATION[0001]This application claims priority to U.S. Provisional Application for Patent No. 60 / 863,167, filed Oct. 27, 2006, and U.S. Provisional Application for Patent No. 60 / 976,188, filed Sep. 28, 2007, the entire disclosures of which are hereby incorporated in their entirely.FIELD OF THE INVENTION[0002]The present invention is concerned with the finding that the macrocyclic quinazoline derivative 4,6-ethanediylidenepyrimido[4,5-b][6,1,12]benzoxadiazacyclo-pentadecine, 17-bromo-8,9,10,11,12,13,14,19-octahydro-20-methoxy-13-methyl, described as compound 22 in PCT publication WO2004 / 105765, is useful in the manufacture of a medicament for the treatment or prevention of bone cancers and methods for killing bone cancer cells, including osteosarcomas, chondrosarcomas, myeloma bone disease and osteolytic bone metastases from other primary sites. It accordingly provides methods for treating, preventing, delaying or mitigating bone cancer, or for preventin...

AI Technical Summary

Benefits of technology

[0016]In related embodiment, the invention provides a method of inhibiting metastatic spread of a cancer to skeletal system, in a mammalian subject comprising administering to a mammalian subject suspected of having metastatic cancer a compound of the invention, in an amount effective to inhibit metastatic spread of the cancer to the skeletal system; and a method for treating bone cancer comprising administering to a mammalian subject diagnosed with a cancer a composition comprising a compound of the invention, in an amount effect to reduce growth or neoplastic spread of the bone cancer. It will be appreciated that any reduction in the rate of cancer growth or spread (which can prolong life and quality of life) is indicative of successful treatment. In preferred embodiments, cancer growth is halted completely. In still more preferred embodiments, cancers shrink or are eradicated entirely. Preferred subjects for treatment are human subjects, but other animals, especially murine, rat, bovine, porcine, primate, and other model systems for cancer treatment, are contemplated. Metastatic cancers as used herein are contemplated to include a variety of cancers can metastasize to the bone, but the most common metastasizing cancers are breast, lung, renal, multiple myeloma, thyroid and prostate. By way of example, other cancers that have the potential to metastasize to bone include but are not limited to adenocarcinoma, blood cell malignancies, including leukemia and lymphoma; head and neck cancers; gastrointestinal cancers, including stomach cancer, colon cancer, colorectal cancer, pancreatic cancer, liver cancer; malignancies of the female genital tract, including ovarian carcinoma, uterine endometrial cancers and cervical cancer; bladder cancer; brain cancer, including neuroblastoma; sarcoma, osteosarcoma; and skin cancer, including malignant melanoma and squamous cell cancer. The present invention especially contemplates prevention and treatment of tumor-induced osteolytic lesions in bone

[0018]In one variation, the subject to be treated has been diagnosed with an operable tumor, and the administering step is performed before, during, or after the tumor is resected from the subject. Compound treatment in conjunction with tumor resection is intended to reduce or eliminate regrowth of tumors from cancer cells that fail to be resected.

Problems solved by technology

The prognosis is often poor and within 1 year after commencing definitive therapy, about 30% of patients diagnosed with osteosarcoma will develop lung metastasis.

Patients developing recurrent disease often have a poor prognosis and die within 1 year of the development of metastatic disease.

Chemotherapy is often ineffective, resulting in a high mortality rate.

Many different treatment options are available or in development, but there is neither a cure nor agreement on an optimal myeloma management regimen.

Unfortunately, dramatic reduction in the number of myeloma cells does not necessarily translate into longer remissions or survival times, and therapies that were effective before a remission may not prove effective upon relapse of the disease.

This balance is upset in myeloma patients, and more bone is resorbed than produced.

Third-generation bisphosphonates are currently under development, but even improved versions of the drugs may have potential side effects including hypocalcemia, kidney damage, and increased pain.

Patients with bone metastases experience considerable morbidity, including bone pain, pathological fractures, hypercalcaemia, reduced mobility and spinal cord or nerve root compression.

Despite the importance of these clinical problems, there are few available treatments for bone loss associated with cancer metastasis.

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